Cannabinoids isolated from Cannabis sativa have been recognized for centuries as therapeutic agents. For example, they have been utilized in treating analgesia, muscle relaxation, appetite stimulation, and anti-convulsion. Recent studies also indicate their potential therapeutic effects in treating cancer and alleviating the symptoms of chronic inflammatory diseases, such as rheumatism and multiple sclerosis.
The actions of cannabinoids are mediated by at least two types of the cannabinoid receptors, CB1 and CB2 receptors, both of which belong to the G-protein-coupled receptor (GPCR) superfamily. CB1 receptor is predominantly expressed in brain to mediate inhibition of transmitter release and CB2 receptor is primarily expressed in immune cells to modulate immune response. See Matsuda et al., Nature (1990) 346:561 and Munro et al., Nature (1993) 365:61.
Compared to other GPCRs, CB1 receptor is typically expressed at higher levels. In the central nervous system, it is highly expressed in cerebral cortex, hippocampus, basal ganglia, and cerebellum, but has relatively low levels in hypothalamus and spinal cord. See, e.g., Howlett et al., Pharmacol Rev (2002) 54:161. Its functions affect many neurological and psychological phenomena, such as mood, appetite, emesis control, memory, spatial coordination muscle tone, and analgesia. See, e.g., Goutopoulos et al., Pharmacol Ther (2002) 95:103. Other than the central nervous system, it is also present in several peripheral organs, such as gut, heart, lung, uterus, ovary, testis, and tonsils. See, e.g., Galiègue et al., Eur J Biochem (1995) 232:54.
CB2 receptor is 44% identical to CB1 receptor with a 68% identity in the trans-membrane regions. See Munro et al., Nature (1993) 365:61. Compared to CB1 receptor, CB2 receptor has a more limited distribution with high expression in spleen and tonsils, and low expression in lung, uterus, pancreas, bone marrow, and thymus. Among immune cells, B cells express CB2 receptor at the highest level, followed in order by natural killer cells, monocytes, polymorphonuclear neutrophils, and T lymphocytes. See Galiègue et al., Eur J Biochem (1995) 232:54. Activation of CB2 receptor has been shown to have analgesic effects in inflammatory models involved in neurodegeneration diseases (such as Alzheimer's disease), and play a role in the maintenance of bone density and progression of atherosclerotic lesions. See, e.g., Malan et al., Pain (2001) 93:239; Benito et al., J Neurosci (2003) 23:11136; Ibrahim et al., Proc Natl Acad Sci USA (2003) 100:10529; Idris et al., Nat Med (2005) 11:774; and Steffens et al., Nature (2005) 434:782.